Calcineurin

Klee, Claude B.; Draetta, Giulio; Hubbard, Michael J.

doi:10.1002/9780470123072.ch4

Cited by 172 publications

(98 citation statements)

References 133 publications

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“…This complex then binds to an intracellular molecule called calcineurin, leading to an inhibition of its activity, and hence inhibiting T cell activation (7). Calcineurin is formed by two subunits: A, which is a catalytic subunit (CnA) responsible for its phosphatase activity, and B, a regulatory subunit (CnB) that is particularly responsive to intracellular calcium and regulates CnA activation (8)(9)(10)(11).…”

Section: Structure and The Mechanism Of Action Of Cnismentioning

confidence: 99%

Calcineurin Inhibitors: 40 Years Later, Can’t Live Without …

Azzi

Sayegh

Mallat

2013

The Journal of Immunology

285

210

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Calcineurin inhibitors (CNIs) revolutionized the field of organ transplantation and remain the standard of care 40 years after the discovery of cyclosporine. The early impressive results of cyclosporine in kidney transplant recipients led to its subsequent use in other organ transplant recipients and for treatment of a variety of autoimmune diseases as well. In this review, we examine the discovery of CNIs, their mechanism of action, preclinical and clinical studies with CNIs, and the usage of CNIs in nontransplant recipients. We review the mechanisms of renal toxicity associated with CNIs and the recent efforts to avoid or reduce usage of these drugs. Although minimization strategies are possible, safe, and of potential long-term benefit, complete avoidance of CNIs has proven to be more challenging than initially thought.

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Section: Structure and The Mechanism Of Action Of Cnismentioning

confidence: 99%

Calcineurin Inhibitors: 40 Years Later, Can’t Live Without …

Azzi

Sayegh

Mallat

2013

The Journal of Immunology

285

210

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“…C alcineurin, a Ser͞Thr protein phosphatase sensitive to Ca 2ϩ and calmodulin, plays a critical role in coupling Ca 2ϩ signals to cellular responses (1,2). The calcineurin heterodimer consists of catalytic and regulatory subunits, A and B (1).…”

mentioning

confidence: 99%

Calcineurin regulates bone formation by the osteoblast

Sun

Blair

Peng

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

146

108

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Two of the most commonly used immunosuppressants, cyclosporine A and tacrolimus (FK506), inhibit the activity of a ubiquitously expressed Ca 2؉ ͞calmodulin-sensitive phosphatase, calcineurin. Because both drugs also cause profound bone loss in humans and in animal models, we explored whether calcineurin played a role in regulating skeletal remodeling. We found that osteoblasts contained mRNA and protein for all isoforms of calcineurin A and B. TAT-assisted transduction of fusion protein TAT-calcineurin A␣ into osteoblasts resulted in the enhanced expression of the osteoblast differentiation markers Runx-2, alkaline phosphatase, bone sialoprotein, and osteocalcin. This expression was associated with a dramatic enhancement of bone formation in intact calvarial cultures. Calcineurin A␣ ؊/؊ mice displayed severe osteoporosis, markedly reduced mineral apposition rates, and attenuated colony formation in 10-day ex vivo stromal cell cultures. The latter was associated with significant reductions in Runx2, bone sialoprotein, and osteocalcin expression, paralleled by similar decreases in response to FK506. Together, the gain-and loss-of-function experiments indicate that calcineurin regulates bone formation through an effect on osteoblast differentiation.FK506 ͉ osteoporosis ͉ runx-2

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“…One of the transducers of the calcium signal system is the calcium/ calmodulin-dependent serine/threonine protein phosphatase 2B, calcineurin, which may also be involved in calcium signalling in mammalian oocyte activation. Calcineurin is composed of two subunits -A subunit, which has a catalytic function, and B subunit, which has a regulatory function (Klee et al, 1988). In mammals, calcineurin A is expressed mainly in the brain but has also been identified in other tissues, such as bone, heart and kidneys.…”

Section: Introductionmentioning

confidence: 99%

“…It mainly participates in signal transduction from the cell membrane to the nucleus, where it regulates transcription (Klee et al, 1988;Liu et al, 1991). In oocytes, the role of calcineurin has been demonstrated during the regulation of meiotic maturation (Drosophila -Takeo et al, 2006 andpig -Petr et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin role in porcine oocyte activation

Tůmová

Eva

Žalmanová

et al. 2016

animal

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Calcineurin is required for oocyte exit from meiotic block in metaphase II (MII) stage in invertebrates and also in lower vertebrates. However, the role of calcineurin in mammalian oocyte activation is still unclear. The aim of this study was to determine whether calcineurin is involved in the processes regulating porcine oocyte activation. Indirect immunofluorescence demonstrated localization of both calcineurin subunits, CnA and CnB, especially in the cortex area of MII oocytes, in vitro fertilized and also parthenogenetically activated oocytes. After activation, the fluorescence intensity of the protein in the cortex area of oocytes remains unchanged; the protein calcineurin in the cytoplasm was recorded mainly around the pronuclei. Treatment of matured oocytes with calcineurin inhibitors, cyclosporin A (CsA) and hymenistatin I (HS-I), followed by activation with calcium ionophore A23187, significantly decreased the rate of activated oocytes compared to oocytes that were treated only with calcium ionophore (Ca-Io), (CsA + Ca-Io 25.0% v. Ca-Io 83.3%; HS-I + Ca-Io 32.5% v. Ca-Io 85.0%). Compared to the control, CsA treatment of matured oocytes followed by activation with Ca-Io did not affect the activity level of metaphase-promoting factor (MPF) and mitogen-activated protein kinase (MAPK) in activated oocytes evaluated by kinase activity assay. Simultaneous staining of calcineurin and cortical granule content in matured oocytes showed that calcineurin distributed in the cortical area of the oocyte has not been colocalized with cortical granules content. On the other hand, the calcineurin inhibition before parthenogenetic activation leads to a reduction of the cortical reaction level compared to oocytes that were not treated with CsA (complete exocytosis: CsA + Ca-Io 2.6% v. Ca-Io 83.9%; sum of cortical granule brightness: CsA + Ca-Io 0.69 v. Ca-Io 0.15). Our results showed that calcineurin is involved in the process of pig oocyte activation and cortical granule exocytosis; however this regulation seems to be MPF and MAPK independent.

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Calcineurin

Cited by 172 publications

References 133 publications

Calcineurin Inhibitors: 40 Years Later, Can’t Live Without …

Calcineurin Inhibitors: 40 Years Later, Can’t Live Without …

Calcineurin regulates bone formation by the osteoblast

Calcineurin role in porcine oocyte activation

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